Article Figures & Data
Figures
- Fig. 1.
Cellular localization of potential SLC targets for the treatment of metabolic disease. SLC transporters are expressed in the plasma membrane or intracellular membranes. Of the five presented SLC families, which are displayed in different colors, 13 members have been assessed to exhibit strong evidence of association with metabolic disease based on human studies and mouse models. The equal shapes of the transporter symbols do not correspond to the different modes of transport, but the arrows indicate transport direction, for example, whether the transporter is proposed to mediate influx of its substrates into the cell (SLC5A1, SLC5A2, SLC13A5) or intracellular compartments (SLC25A7, SLC25A8, SLC25A9, SLC30A8), facilitates both influx and efflux (SLC16A1, SLC16A11, SLC16A13), or acts as an exchanger (SLC25A13, SLC25A20, SLC25A24). The main substrates of the transporters are indicated next to the transporter symbol, except for SLC16A13, which is not characterized at all concerning substrate specificity and transport mode.
- Fig. 2.
Tissue distribution of potential SLC targets for the treatment of metabolic disease. SLC transporters are broadly expressed. The 13 SLCs, which belong to five families displayed in different colors and were evaluated to have strong potential as targets for the treatment of metabolic disease, are highly expressed in metabolically active organs such as the liver, kidney, brain, and intestine.
Tables
- TABLE 1
Potential SLC targets for the treatment of metabolic disease with strong evidence based on human studies and mouse models
SLC Name Protein Name Substrates Expression in Metabolically Active Organs Subcellular Localization Link to Metabolic Disease in Humans Link to Metabolic Disease in Mice References SLC5A1 SGLT1 Glucose, galactose Kidney, intestine Plasma membrane Glucose/galactose malabsorption Glucose/galactose malabsorption, impaired glucose tolerance Turk et al., 1991; Martin et al., 1996; Kasahara et al., 2001; Wright et al., 2011; Powell et al., 2013; Wright, 2013 SLC5A2 SGLT2 Glucose Kidney Plasma membrane Familial glucosuria Obesity, insulin resistance, diabetes Santer et al., 2000, 2003; van den Heuvel et al., 2002; Jurczak et al., 2011; Wright et al., 2011; Powell et al., 2013; Wright, 2013 SLC13A5 NaCT, NaC2, INDY Citrate, succinate, malate, fumarate Liver, brain, adrenal glands Plasma membrane Obesity, NAFLD Obesity, fatty liver, insulin resistance Birkenfeld et al., 2011; Bergeron et al., 2013; Pesta et al., 2015; Brachs et al., 2016; von Loeffelholz et al., 2017b SLC16A1 MCT1 Lactate, pyruvate, ketone bodies Intestine, heart, skeletal muscle, liver, kidney, adrenal glands, brain, adipose tissue Plasma membrane Ketoacidosis, exercise- induced hyperinsulinemia Exercise-induced hyperinsulinemia, obesity, insulin resistance, hepatic steatosis Halestrap and Meredith, 2004; Otonkoski et al., 2007; Pullen et al., 2012; Lengacher et al., 2013; van Hasselt et al., 2014; Balasubramaniam et al., 2016; Carneiro et al., 2017 SLC16A11 MCT11 Pyruvate Thyroid, liver Endoplasmic reticulum, plasma membrane T2D Fatty liver, insulin resistance, diabetes Williams et al., 2014; Lara-Riegos et al., 2015; Traurig et al., 2016; Rusu et al., 2017; Almeda-Valdes et al., 2019; Hidalgo et al., 2019; Zhao et al., 2019b SLC16A13 MCT13 Unknown Liver, kidney, intestine Golgi apparatus T2D N.A. Hara et al., 2014; Williams et al., 2014 SLC25A7 UCP1, thermogenin H+ Brown adipose tissue Inner mitochondrial membrane Obesity, T2D Obesity Nicholls et al., 1978; Lowell et al., 1993; Kopecky et al., 1995; Kopecký et al., 1996a,b; Baumruk et al., 1999; Li et al., 2000; Palmieri, 2004; Gates et al., 2007; Brondani et al., 2012 SLC25A8 UCP2, UCPH H+ Adipose tissue, skeletal muscle, liver, kidney, pancreas, heart Inner mitochondrial membrane Obesity, T2D Obesity Fleury et al., 1997; Gimeno et al., 1997; Arsenijevic et al., 2000; Zhang et al., 2001; Palmieri, 2013; Dalgaard, 2011 SLC25A9 UCP3 H+ Skeletal muscle Inner mitochondrial membrane Obesity, T2D Obesity Boss et al., 1997; Lowell, 1999; Clapham et al., 2000; Gong et al., 2000; Vidal-Puig et al., 2000; Horvath et al., 2003; Jia et al., 2009; Palmieri, 2013 SLC25A13 AGC2, CTLN2, citrin aralar 2 Aspartate, glutamate Liver, kidney, intestine, brain, pancreas, heart, skeletal muscle, adrenal glands Inner mitochondrial membrane NICCD, CTLN2 Citrullinemia Kobayashi et al., 1999; Ohura et al., 2001; Tazawa et al., 2001; Sinasac et al., 2004; Saheki and Song, 2005; Takagi et al., 2006; Tsai et al., 2006; Saheki et al., 2007; Fukumoto et al., 2008; Komatsu et al., 2008; Chang et al., 2011; Palmieri, 2013; Hayasaka et al., 2018 SLC25A20 CAC, CACT Carnitine, acylcarnitine Liver, intestine, adrenal glands, heart, skeletal muscle, kidney, brain, pancreas Inner mitochondrial membrane Carnitine carrier deficiency N.A. Huizing et al., 1997; Indiveri et al., 2011; Palmieri, 2013 SLC25A24 APC1, MCSC1, SCAMC1 Adenine nucleotides, phosphate Intestine, adipose tissue, adrenal glands, liver, pancreas, kidney Inner mitochondrial membrane Obesity Obesity Palmieri, 2013; Urano et al., 2015; Palmieri and Monne, 2016 SLC30A8 ZnT8 Zinc Pancreas Secretory granule T2D Obesity, insulin resistance Chimienti et al., 2004; Saxena et al., 2007; Scott et al., 2007; Sladek et al., 2007; Boesgaard et al., 2008; Nicolson et al., 2009; Pound et al., 2009, 2012; Tamaki et al., 2009, 2013; Cauchi et al., 2010; Wijesekara et al., 2010; Kim et al., 2011; Flannick et al., 2014; Gerber et al., 2014; Shan et al., 2014; Maruthur et al., 2015; Rutter and Chimienti, 2015; Mitchell et al., 2016; Li et al., 2017a, 2018; Wong et al., 2017; Ding et al., 2018; Dong et al., 2018; Kleiner et al., 2018; Lin et al., 2018; Liu et al., 2018; Plengvidhya et al., 2018 - TABLE 2
Potential SLC targets for the treatment of metabolic disease with limited evidence based on human studies or mouse models
SLC Name Protein Name Substrates Expression in Metabolically Active Organs Subcellular Localization Link to Metabolic Disease in Humans Link to Metabolic Disease in Mice References SLC5A9 SGLT4 Mannose, glucose, fructose Intestine, kidney, liver Plasma membrane Diabetic retinopathy N.A. Tazawa et al., 2005; Ung et al., 2017 SLC5A10 SGLT5 Mannose, fructose, glucose, galactose Kidney Plasma membrane N.A. Hepatic steatosis Grempler et al., 2012; Fukuzawa et al., 2013 SLC13A1 NaS1, NaSi-1 Sulfate, thiosulfate, selenate Kidney, intestine, adrenal glands, adipose tissue Plasma membrane Drug-induced hepatotoxicity Fatty liver Markovich, 2001; Dawson et al., 2006 SLC13A2 NaDC1, NaC1, SDCT1 Succinate, α-ketoglutarate, citrate Kidney, intestine Plasma membrane Nephrolithiasis Nephrolithiasis Markovich and Murer, 2004; Ho et al., 2007; Bergeron et al., 2013; Udomsilp et al., 2018 SLC13A3 NaDC3, NaC3, SDCT2 Succinate, α-ketoglutarate, citrate Kidney, liver, brain Plasma membrane Diabetic nephropathy, chronic kidney disease N.A. Bento et al., 2008; Ju et al., 2009; Bergeron et al., 2013; Nanayakkara et al., 2014 SLC16A3 MCT4 Lactate, pyruvate, ketone bodies Skeletal muscle, brain, intestine Plasma membrane, nuclear membrane Diabetic nephropathy N.A. Lokman et al., 2011; Halestrap, 2013 SLC16A9 MCT9 Carnitine Kidney, adrenal glands Plasma membrane Gout N.A. Kolz et al., 2009; van der Harst et al., 2010; Halestrap, 2013; Nakayama et al., 2013 SLC16A10 MCT10, TAT1 Aromatic amino acids Skeletal muscle, heart, kidney, intestine, pancreas Plasma membrane NAFLD N.A. Halestrap, 2013; Lake et al., 2015 SLC25A25 APC2, SCaMC-2, MCSC Adenine nucleotides, phosphate Brain, heart, skeletal muscle, liver, intestine, pancreas Inner mitochondrial membrane N.A. Obesity Anunciado-Koza et al., 2011 SLC25A40 MCFP Unknown Liver, kidney, intestine, brain, adrenal glands Inner mitochondrial membrane Hypertriglyceridemia N.A. Rosenthal et al., 2013 SLC30A3 ZnT3 Zinc Brain Synaptic vesicle N.A. Impaired glucose tolerance Palmiter et al., 1996; Smidt et al., 2009; Keele et al., 2018 SLC30A7 ZnT7 Zinc Intestine Golgi apparatus N.A. Obesity, insulin resistance Kirschke and Huang, 2003; Huang et al., 2007, 2010, 2012, 2018
In this issue
SLC Transporters as Targets to Treat Metabolic Disease
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- Article
- Abstract
- I. Introduction
- II. Solute Carrier Membrane Transport Proteins
- III. Links to Human Metabolic Disease and Potential Targets
- IV. Proposed Requirements for Metabolic Target Structures
- V. Emerging Potential of Other Solute Carrier Target Structures
- VI. Conclusion and Outlook
- Acknowledgments
- Authorship Contributions
- Footnotes
- Abbreviations
- References
- Figures & Data
- Info & Metrics
- eLetters
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